HHBM 


COLUMBIA  LIBRARIES  OFFSITE 

HEALTH  SCIENCES  STANDARD 


HX64121739 
RC261  .B291914   Review  of  recent  can 


RECAP 


Bashford,  E.F. 

Review  of  Recent  Cancer 
Research.  191u, 


intljeCttpoflettJgork 


Digitized  by  tine  Internet  Arciiive 

in  2010  witin  funding  from 

Open  Knowledge  Commons 


http://www.archive.org/details/reviewofrecentcaOObash 


PROCEEDINGS 


OF  THE 


NEW  YORK  PATHOLOGICAL 
SOCIETY 


REVIEW  OF  RECENT  CANCER  RESEARCH 


BY 


DR.  E.  F.  BASHFORD 

Director  of  the  Laboratory,  Imperial  Cancer  Research  Fund,  London 


MIDDLETON  GOLDSMITH  LECTURE 
I912 


PRESS  OF 

THE  NEW  ERA  PRINTING  COMPANr 

LANCASTER.  PA. 


REVIEW  OF 
RECENT  CANCER  RESEARCH 


BY 


DR.  E.  F.  BASHFORD 

Director  of  the  Laboratory,  Imperial  Cancer  Researcii  Fund,  London 


MIDDLETON  GOLDSMITH  LECTURE 
I912 


3^1 


REMEW   OE   RECENT   CAXXER   RESEARCH^ 

Lecture  I. 

Statistical  and  Comparative  Ixvestigatioxs 

The  recent  advances  made  in  our  knowledge  of  cancer  may 
be  grouped  together  according  as  they  have  been  obtained  by 
statistical  or  by  experimental  methods.  In  this  first  lecture  1 
shall  direct  your  attention  to  the  results  which  have  been  obtained 
by  improving  the  national  statistics  of  England  instead  of  taking 
a  separate  cancer  census  as  was  done  in  Germany  and  other  coun- 
tries, and  to  certain  other  statistical  observations.  In  the  second 
lecture  I  shall  discuss  the  results  of  experiments. 

A  few  general  remarks  are  necessary  to  introduce  the  statis- 
tical details.  It  is  essential  that  the  great  frequency  of  cancer 
should  be  borne  in  mind,  because  this  of  itself  explains  why 
aggregations  of  cases  are  bound  to  occur.  Cancer  is  so  frequent 
in  England  that  one  out  of  every  seven  women  and  one  out  of  less 
than  e\'ery  eleven  men  above  the  age  of  35.  ultimately  dies  of  it. 
On  this  basis  it  is  possible  to  calculate-  how  often  one,  two, 
three,  or  more,  cases  of  cancer  may  be  expected  in  a  family.  Of 
100  families  each  of  six  members.  3  males  and  3  females,  no 
case  of  cancer  would  be  expected  in  51,  one  case  would  be  ex- 
pected in  36,  two  cases  in  11,  and  3  or  more  cases  in  2  families. 
Of  100  families  of  eight  members,  four  women  and  four  men.  no 
case  would  occur  in  41,  one  in  39,  2  in  16  and  3  or  more  in  four 
families.  In  100  families  of  ten  members,  five  men  and  five 
W(jmen,  only  33  would  1)e  expected  to  escape  altogether,  whereas 
there  would  be  one  case  in  39,  two  in  20,  and  3  or  more  in  eight 
families.     Moreover,  the  disea.se  is  ten  times  as  frequent  at  70 


■    ^Middleton   Goldsmith   Lectures  delivered   before  tlie   Xcw  York   Patho- 
logical Society,  October  2  and  4,  ii>i_'. 

2  Calculation  made  on  the  l)asis  ni  i  in  8  and  i  in  11  respectively. 

1 


2  REVIEW    OF    RECENT    CANCER    RESEARCH 

as  at  35  years  of  age;  therefore  similar  calculations  made  for  age 
periods  other  than  35  would  show  a  corresponding  greater  liabil- 
ity than  the  a^•erages  set  forth  above.  Hence  aggregations  of 
cases  of  cancer  to  have  any  significance  at  all  must  occur  with  a 
frequency  which  removes  them  from  all  possibility  of  their  being 
merely  what  would  be  expected  owing  to  the  great  frequency  of 
the  disease.  In  the  course  of  years  it  is  quite  natural  that  a 
number  of  cases  should  occur  in  a  village,  a  street,  a  house,  or 
even  a  family  which  has  inhabited  the  same  house  for  genera- 
tions, without  the  numbers  necessarily  meaning  anything  more 
than  what  was  to  be  expected  according  to  the  theory  of  probabil- 
ities. This  criticism  applies  without  exception  to  all  statements 
as  to  cancer  houses,  cancer  streets,  and  cancer  villages,  which  have 
been  adduced  as  evidence  that  cancer  is  infective,  although  I  do 
not  wish  to.be  understood  as  denying  that  cancer  or  rather  cer- 
tain forms  of  it  occurring  on  different  parts  of  the  body,  may, 
and  actually  do,  vary  in  dififerent  areas. 

As  is  apparent  from  the  figures  I  gave  of  the  relative  liability 
of  males  and  females  above  35,  the  relative  frequency  of  cancer  is 
influenced  very  largely  by  the  relative  proportions  of  the  two 
sexes  and  the  respective  numbers  of  each  sex  living  at  each  age- 
period.  If  a  curve  be  constructed  of  the  mortality  from  an 
infective  disease,  c.  g.,  tuberculosis,  and  regard  be  paid  to  the 
different  age-periods,  it  is  at  once  evident  that  the  sacrifice  of  life 
is  already  high  in  the  early  years  of  life.  After  a  fall  the  curve 
rises  till  about  middle-age  and  thereafter  falls  to  the  end  of  life. 
The  curve  is  very  similar  for  the  two  sexes,  although  higher 
throughout  for  males,  as  also  in  the  case  of  typhoid;  but  throw- 
ing the  two  sexes  together  into  one  curve  does  not  materially 
modify  it. 

If  similar  curves  be  constructed  for  cancer  the  appearances 
are  markedly  different.  If  both  sexes  are  lumped  together  and 
age-periods  are  regarded,  cancer  is  of  no  importance  as  a  cause 
of  death  till  25-35  J  but  thereafter  the  curve  rises  progressively 
up  to  the  end  of  life.  If  the  sexes  be  considered  apart  the  curves 
diverge  widely,  that  for  women  being  the  higher.  At  birth  can- 
cer is  more  common  than  at  10-15  years :  this  applies  both  to  car- 


REVIEW    OF    RECENT    CANCER    RESEARCH  O 

cinonia  and  sarcoma  and  can  be  brought  into  connection  with 
developmental  anomalies  in  which  complicated  tumours,  or  sar- 
comata, more  rarely  carcinomata,  have  arisen.  From  the  20th 
year  onwards  the  curve  for  each  sex  rises  progressively,  and  like- 
wise both  for  carcinoma  and  sarcoma.  The  old  teaching  that 
sarcoma  was  a  disease  of  youth  is  untenable;  sarcoma  is  relatively 
more  frequent  in  youth  than  is  carcinoma,  but  both  become  more 
frequent  in  a  parallel  manner  as  life  advances.  The  old  teaching, 
now  shown  to  be  erroneous,  was  due  to  the  statistical  fallacy  of 
generalising  from  hospital  statistics  which  have  no  relation  to  the 
actual  facts  of  population,  its  sex  and  age  constitution. 

The  cur\es  in  which  all  cases  are  thrown  together,  although 
they  give  valuable  information,  conceal  very  important  facts  which 
are  only  revealed  when  curves  are  constructed  not  only  for  each  sex 
at  the  several  age-periods,  but  also  for  each  organ  or  site  of  the 
body.  Then  the  greater  frequency  of  cancer  in  women  is  seen  to 
be  due  to  cancer  of  the  breast  and  uterus.  It  is  also  evident  that 
the  relation  between  age  and  mortality  is  different  for  the  dift'erent 
organs  but  parallel  for  the  same  organ  in  the  two  sexes.  This 
similarity  is  illustrated  by  the  extreme  example  of  the  cancer  of 
the  breast  so  common  in  women,  so  rare  in  men.  The  curves 
are  parallel  and  rise  to  the  end  of  life  in  both  sexes;  the  same 
obtains  for  ilie  liver,  skin,  rectum,  lip,  and  face.  If  dift'erent  organs 
are  compared,  c.  g.,  breast  and  uterus,  the  curve  for  the  uterus 
attains  only  half  the  height  of  that  for  the  Ijreast  according  to 
age,  although  there  is  a  greater  total  mortality  from  cancer  of 
the  uterus  than  for  any  other  single  organ.  This  difference  is 
in  part  explained  because  cancer  of  the  uterus  becomes  a  frequent 
cause  of  death,  and  therefore  causes  more  deaths  at  earlier  ages 
than  does  cancer  of  the  breast.  Nevertheless,  the  curves  l)ring 
out  real  differences  in  the  susceptibility  to  cancer  at  different 
ages  in  the  two  organs;  whereas  the  curve  for  the  breast  rises  to 
the  end  of  life,  that  for  the  uterus  flattens  after  55  and  falls 
progressively  after  65.  .Similar  differences  exist  also  for  other 
organs;  skin,  lij),  and  face  lia\e  typical  cur\-es,  rising  to  the  end 
<if  life,  which  stand  in  sliar])  contrast  to  tlic  c(|na]]\-  tvpical  curves 
for  the  tongue,  liver,  intestines,  stomacli,   which  attain  a  mnxi- 


4  REVIEW    OF    RECENT    CANCER    RESEARCH 

mum  followed  by  a  fall.  For  some  organs  there  is  evidence  of 
two  maxima.  These  differences  in  the  age  incidence  of  cancer 
for  dift'erent  parts  of  the  body  demonstrate  that  in  any  discussion 
of  the  greater  frequency  of  cancer  in  one  area  than  in  another, 
it  is  essential  that  the  different  organs  and  sites  of  the  body  be 
considered  apart  and  not  all  lumped  together. 

The  preceding  considerations  show  the  importance  of  age  and 
the  difference  in  its  influence  for  different  organs.  Even  if  sta- 
tistics alone  are  not  able  to  explain  this  phenomenon,  they  do 
permit  of  the  inference  that  probably  more  than  one  cause  is 
operative  in  the  etiology  of  cancer.  I  shall  have  to  revert  to  this 
subject  when  I  come  to  consider  experimental  methods.  Before 
leaving  this  subject  however,  it  is  important  to  emphasise  that  this 
law  of  age-incidence  is  a  biological  law  which  holds  both  for  long 
and  for  short-lived  animals;  it  is  as  fully  applicaljle  to  the  mouse, 
which  rarely  lives  three  years,  as  it  is  to  man.  Great  as  is  its  sta- 
tistical importance,  its  biological  significance  has  even  a  greater 
heuristic  value.  I  have  applied  it  to  the  several  organs  of  the 
human  body,  where,  for  example,  the  short-lived  chorion  repre- 
sents the  one  extreme  and  skin  the  other,  and  together  with 
Murray  have  urged  that  it  must  be  taken  account  of  in  any  satis- 
factory explanation  of  cancer.  It  would  appear  that  it  is  not 
age  or  senility  of  the  individual  that  is  an  important  contributory 
etiological  factor,  but  rather  senescence  of  the  individual  tissues. 
Further  discussion  of  its  significance  appears  profitless,  till  it  is 
determined  whether  the  fall  which  occurs  for  some  organs  is  a 
real  fall  or  not. 

With  the  exception  of  diabetes,  cancer  alone  of  all  causes  of 
death  exhibits  a  constant  increase  in  the  number  of  deaths  re- 
corded. This  phenomenon  is  a  characteristic  feature  of  mor- 
tality statistics  wherever  they  are  compiled  throughout  the  world. 
In  England,  where  reliable  statistics  are  available  for  the  longest 
series  of  years,  the  death-rate  per  million  living  has  risen  from 
500  in  i860  to  1,060  in  1909,  the  corresponding  figures  for  males 
being  from  200  in  i860  to  820,  in  1909.  Stated  otherwise,  of 
women  above  the  age  of  thirty-five,  one  in  12  was  recorded  as 
dying  of  cancer  in  1889,  but  one  in  seven  in  1909,  and  of  deaths 


REVIEW    OF    RECENT    CANCER    RESEARCH  5 

of  men  one  in  21  in  1889,  but  one  in  almost  10  in  1909.  Stated 
in  this  way  or  exhibited  in  curves  (Figs,  i  and  2)  constructed  on 
this  basis  the  increase  in  the  number  of  deaths  recorded  is  both 
astonishing  and  alarming  and  has  alarmed  both  the  medical  pro- 
fession and  the  public.     But  they  are  crude  statistical  methods. 


Females. 


RATIO^ 

400 


370 


340 


310 


280 


250 


220 


190 


o^RATIO 


100 


17043  J 

Fig.  I. — E.\GL.\.\D  and  \Vale.s. — Cancer.  Ratio  per  cent,  of  mortality  at 
several  age-groups  in  quinquennia  since  1S51-5  to  the  mortality  at  the  same 
age-groups  in  185 1-5. 

From  time  to  time  attempts  have  been  made  to  explain  the  in- 
crease by  the  fall  in  infant  mortality,  the  fall  in  niDrtality  from 
tuberculosis,  and  infective  diseases  in  general.  If  this  were  so, 
then  there  should  l)e  no  increase  if  com])arisons  wore  made  1)0- 


RATIOS 


400 


370 


040 


310 


280 


250 


220 


190 


REVIEW    OF    RECENT    CANCER    RESEARCH 


Males. 


<0 

^O 

^ 

v^ 

^o 

?a 

UJ 

=0 

00 

^ 

§i 

E 

i=5 

=0 

«0 

* 

^ 

di 

CD 

280 


190 


100 


Fig.  2. — England  and  Wales. — Cancer.  Ratio  per  cent,  of  mortality  at 
several  age-groups  in  quinquennia  since  185 1-5  to  the  mortality  at  the  same 
age-groups  in  1851-5. 


tween  a  million  living  at  each  age-period  years  ago  and  to-day. 
However,  when  this  is  done  there  is  still  an  increase,  and  as  a 
matter  of  fact  such  an  explanation  involves  the  grave  statistical 


REVIEW    OF    RECENT    CAXCER    RESEARCH 


RAT£ 
PER 

ACE 

RATE 
PER 

22O0 
?l><7  0l 

I2O0 
IIOO 
1000 
900 
$00 

700 

/ 

1 

1     1     1 

J 

\ 

1 

1 

/ 

iAI 

A 

LIVE 

h 

n 

^ 

\ 

1 

'    \ 

1900 
iBoo 

1700 

1600 

ISoo 

14001 

1300 

1200 
rlOO 
1000 
900 
800 

TOO 

600 

SOO 

300 

200 

100 

0 
1600 

1400 

1200 

1000 

Boo 
600 

4.00 

200 

0 

3eo 
200 
100 

a 

iiiL 

lAI 

ml- 

\     1 

\\\ 

1 

iikis.J 

/ 

600 

Soo 

300 

2O0 

j! 

! 

-1 

: 

— 

- 

i 

! 

R 

rfAst 

J- 

1 

■ 

1 

too 
7O0 
eoo 
Soo 

4-00 
300 
200 
100 
0 

800 
700 
6oo 
Soo 
400 
500 
200 
100 

o 

40O 

3oe 
200 

100 

o 

Joo 

20C 

IOC 

— c 

/ 

\ 

/ 

\J 

-■ 

' 

_i 

rdJ 

'^1 

mf 

/ 

\ 

/' 

N 

! 

/f 

\ 

'  J 

1 

1 

h 

rr 

nil 

1 

ft 

1 

1/ 

1 

/ 

7 

^ 

V 

^ 

/ 

1 

.-, 

^. 

'r- 

- 

1 

''1 

/ 

/ 

y 

/ 

; 

V- 

T 

\r 

F 

// 

I 

IP 

;/ 

V, 

/ 

.*/ 

w 

/ 

f 

/ 

J  / 

\ 

''/ 

/ 

'> 

f 

,, 

/ 

; 

11 

1 

, 

ikri 

IMI 

lOl 

TO^SfiijE 

... 

V\  ' 

\ 

1 

1 1  n 

'' 

/iksAp* 

ATi 

rt 

i 

L_!   / 

1 

1 

U 

"^ 

II 

i 

'     ^'  \ 

— 

,>-^ 

'' 

' 

\      1      i       1 

r^ 

\- 

BlAdDEjUae 

,_ 

. 

1 

_iUREIl|fiA-^ 

1 

nni 

Th 

lAW, 

I     i 

1  1  1  y 

i    i    !    i    :  ^■■ 

■■■^ 

1  . 

'  1  ■■•; 

±. 

1 

---^^>^    '     '     ■  ,-n.l','i— ^-^ 

1  .. 

PXii— ^— 1 

riAucs 


FenAiti 


Fio.  3. — E.N'fiLAND  AND  Wales. — Canccr.     Age  and  sex  mortality  I  mm  cancer 
of  various  parts  of  the  body.     1901-g. 


8 


REVIEW    OF    RECENT    CANCER    RESEARCH 


error  of  confounding  death-rates  with  total  deaths.  It  is  quite 
true  more  people  reach  the  cancer  ages  but  the  question  is,  Do  a 
higher  proportion  of  them  die  of  cancer  than  did  fifty  years 
ago  ?  A  further  question  is  :  Why  has  the  increase  been  greater 
in  men  than  women? 


RftTE  t^         to 


8      5 


MILLIOn- 
225   . 


2/0 

195 

180 

165 

150 

135 

IZO 

105 

90 

75 

60 

4-5 

30 

15 

0 


LIVERi  GALL  BLADE  TR. 


UTERU; 


um-s^uf:g^^ 


■    FECTlifT 


CVAR 


SKlfl 


CO         <n         o  RATE 

O  O  —    pro 

MILUOrt 
225 

210 

135 

180 

165 

150 

135 

120 

105 

9C 

75 

60 

45 

30 

t5 

0 


P'lG.  4. — England  and  Wales. — Cancer  of  various  parts  of  the  body;   mor- 
tality at  all  ages,  1897-igio.     Females. 


The  problem  ought  no  longer  to  be  approached  by  throwing 
all  cases  of  cancer  together  as  if  cancer  could  be  treated  statistic- 
ally like  an  infective  disease,  as  is  done  even  to-day  by  many  of 


REVIEW    OF    RECENT    CAXCER    RESEARCH 


0 


those  who  pre-judge  what  the  future  still  has  in  store  regarding 
the  etiolog}'  of  cancer,  by  refusing  to  entertain  any  other  possi- 
bility than  that  of  a  living  virus. 

Instead  of  lumping  all  cases  of  cancer  together,  each  organ 
and  site  must  be  considered  separately  (Fig.  3).  When  that  is 
done  partially  and  the  female  generative  organs   (Fig.  4)   con- 

Dcaths 


KATE  r- 
PER  2 

llUJOfl- 
195 

a. 
en 

CO 

a- 

V 

oc 

0 
0 

0 
35 

0 

a 

01 

0 
01 

2 

Q 
2 

§ 

2 

I 

0 
2 

KAT£ 

PER 

niLLIOf 

180 

\m 

165 

^ 

^.^ 

.■^ 

165 

150 

y' 

STor' 

ACH. 

(sn 

135 



i.i.*; 

IZO 

" 

IPO 

105 

/o? 

^ 

r;ALL 

"rTat) 

< 

\ 

^^ 

-^ 



90 

1 

Vfr/ 

<)0 

75 

..--•■ 

7.S 

60 

•  ■'" 

RECT 

;n. 

y^ 

-^^ 

^.^- 

60 

49 

•■■' 



Ti 

rte's"" 

mE5. 

-'' 

, 

4.5 





TONG 

JL. 

30 

^0 

ts 

5KI 

n. 

IS 

0 

0 

Fjg. 


-England  and  \\'.\Lh>. — Cancer  oi   various  parts  of  the  body;   mor- 
tality at  all  ages,  1897-1910.     Males. 


sidercd  apart  from  the  rest  of  the  Ixxly.  it  is  at  once  apparent  that 
they  have  not  shown  so  great  an  increase  as  the  rest  of  the  bodv. 
I'or  long  it  was  pleaded  that  llic  expense  would  be  nut  of  all 
proportion  to  the  l)enelit  which  would  follow  from  tabulating  the 
several  organs  and  sites  of  the  l)ody  sc[)aralcly ;  1)ul  the  luiglish 


10 


REVIEW    OF    RECENT    CANCER    RESEARCH 


national  statistical  office  and  the  Imperial  Cancer  Research  Fund 
have  at  last  obtained  this  separation,  and  these  data  are  available 
from  1 90 1  (really  1897)  onwards  for  50  different  sites.  The 
figures  definitely  prove  how  unequally  the  different  parts  of  the 
body  share  in  the  increase  in  the  number  of  deaths  recorded. 
For  some  parts  of  the  body  there  has  been  no  increase  at  all  dur- 
ing the  past  13  years,  c.  g.,  the  skin,  liver  and  gall  bladder  in 
both  sexes  (Figs.  4  and  5)  ;  the  uterus  and  ovary  show  little  or  no 
increase  in  contrast  to  the  breast,  for  which  there  is  an  increase 
of  28  per  cent.  The  greatest  increase  in  both  sexes  is  for  the 
stomach  and  intestines,  and  it  cannot  be  considered  apart  from 
the  standstill  of  the  figures  for  the  liver,  where  primary  cancer 
is  known  to  be  so  rarely  observed  at  autopsy.  In  this  particular 
case  it  is  quite  obvious  we  have  to  do  with  better  diagnosis  and  a 
more  accurate  certification  of  the  causes  of  death  whereby 
growths  previously  referred  to  the  secondary  site  are  now  allo- 
cated to  the  primary  site.  The  question  of  the  importance  of 
these  factors  has  often  been  discussed,  and  the  influence  of  the 


Analysis  of  the  Cases  of  Neiv  Groivths  reported  by  tlie  Hospital  Authorities 
(Microscopical  Examination  has  been  made  in  all  Cases),  1904-09,  all  Ages 


Malignant  N 

ew  Growths 

Wrongly  Diagnosed 

Correctly  Diagnosed 

Not  Diagnosed 

as  Cancer 

Accessible 

Inaccessible 

Intermediate 

5,854 
1. 555 
1,322 

S67 
945 
289 

488 

IS9 
160 

Total 

8,731 

1,801 

757 

Accessible 

Inaccessible 

Intermediate 

Accessible 

91.1% 
62.3% 
82.0% 

93.0% 
90.7% 
89.2% 

8.9% 
37.8% 
18.0% 

7.0% 

9.3% 

10.8% 

Intermediate 

accuracy  of  diagnosis  may  be  illustrated  by  the  results  of  a  com- 
parison of  the  clinical  diagnoses  with  the  pathological  and  his- 
tological findings  for  13,000  cases  treated  in  London  hospitals. 
The  circumstances  under  which  these  diagnoses  were  made 
are  much  more  favoural)le  than  obtain  among  the  population  in 


REVIEW    OF    RECENT    CANCER    RESEARCH  11 

general,  and  it  should  be  noted  that  the  increase  in  deaths  affects 
mainly  those  internal  parts  of  the  body  where  diagnosis,  as  the 
abo\e  table  shows,  is  dit^cult,  or  formerly  was  impossible  before 
the  introduction  of  autopsies,  the  great  advances  of  surgery  and 
histolog}-.  These  factors  account  in  part,  if  not  wholly,  for 
the  greater  increase  in  men,  when  all  cases  of  cancer  are  con- 
sidered together,  for  in  them  cancer  is  more  often  internal. 
They  must  be  given  due  weight  even  if  the  almost  equal  import- 
ance of  the  improvement  in  certification  of  causes  of  death,  and 
in  the  accuracy  of  statistics  of  population  as  a  whole  and  of 
improved  statistical  methods  is  taken  full  account  of.  For  some 
parts  of  the  body  no  increase  has  taken  place,  for  other  parts 
the  increase  can  be  explained,  if  not  wholly,  at  anv  rate,  largelv. 
by  the  foregoing  considerations.  ])ut  for  other  sites,  c.  g.,  the 
tongue  in  man  and  the  breast  in  women,  the  explanation  is  not  so 
easy.  Comparative  investigations  have  shown  how  the  relative 
anatomical  distribution  of  cancer  in  the  body  is  modified  by  other 
diseases  c.  g.,  Biharziosis.  or  by  the  practice  of  peculiar  customs 
l)y  aboriginal  races,  and  there  is  ever}-  justification  for  conclud- 
ing that  the  adopti(jn  of  these  customs  in  America  or  in  England 
would  at  once  become  responsible  for  a  large  increase  of  cancer 
in  sites  in  which  it  is  rare  or  does  not  occur  at  all.  Hence  the 
possibility  of  variations  in  the  relative  proportions  of  cases  of 
cancer  occurring  in  different  parts  of  the  body  or  in  different 
areas  even  in  the  same  country,  from  time  to  time,  must  be  ad- 
mitted. In  any  case  it  is  still  too  soon  to  conclude  that  for  all 
parts  of  the  body  the  accuracy  of  diagnosis  and  of  certification 
of  causes  of  death  had  increased,  but  cancer  itself  had  not  in- 
creased for  any  single  site  or  organ,  although  this  exi)lanati(m 
certainly  holds  for  the  mouse.  In  1896  Tivingood  described  in 
America  two  cases  of  carcinoma  in  a  mouse,  but  tweU'c  vears 
ago  not  a  single  case  had  been  recorded  in  F.ngland  or  in  Ger- 
many. To-day,  about  1,000  cases  each  ha\"e  been  recorded  from 
Khrlich's  laboratory  in  Frankfort,  and  the  Imperial  Cancer  Re- 
search Fund  in  London.  \\'hy?  Sim])ly  because  the  disease 
has  been  looked  for  and  found  where  previously  it  was  unsus- 
pected.      The  same  remarks  apply  in  my  personal  experience  to 


12  REVIEW    OF    RECENT    CANCER    RESEARCH 

the  COW,  which  is  very  hable  to  several  forms  of  cancer.  It 
may  be  asserted  that  it  is  quite  wrong  to  talk  about  an  increase  of 
cancer  in  general,  and  to  frighten  the  public  unduly  by  extrava- 
gant statements  based  upon  figures  unworthy  of  the  name  of  sta- 
tistics. I  am  sorry  to  say  this  criticism  applies  with  force  to  the 
United  States  where  the  registration  of  births  and  deaths  is  so 
imperfect  and  the  difficulties  bound  up  with  the  large  floating 
population  partly  inseparable  from  the  vast  amount  of  immigra- 
tion such  that,  combined,  they  render  any  comparison  between 
the  past  and  the  present  or  between  different  States  impossible. 
My  remarks  will  have  made  it  evident  that  the  question  of  the 
increase  of  cancer  cannot  be  discussed  in  general  terms  on  the 
basis  of  lumping  all  cases  together  and  stating  them  as  so  many 
dcatJis  per  i,ooo  or  100,000  of  population,  no  regard  being  taken 
of  age  and  sex,  which  is  the  only  method  available  for  the 
United  States.  I  am  sorry  to  say  it  is  possible  for  me  to  draw 
more  reliable  conclusions  as  to  the  incidence  of  cancer  in  the 
nati\'es  of  some  British  colonies  than  in  the  population  of  New 
York. 

In  considering  the  real  or  apparent  increase  of  cancer,  it  is 
necessary  to  regard  the  different  parts  of  the  body  separately  for 
other  reasons,  since  it  has  been  asserted,  especially  in  Germany, 
that  its  most  anxious  aspect  was  that  the  increase  affects  mainly 
the  younger  ages.  This  is  certainly  not  the  case  in  England  and 
I  ha^■e  not  found  reliable  evidence  that  it  is  so  in  Germany.  The 
accompan3nng  tables  show  quite  distinctly  that  in  England  it  is 
the  higher  age-periods  that  are  chiefly  affected.  This  fact  is  not 
so  remarkable  if  the  relati\e  proportions  of  persons  dying  of 
"old  age"  is  compared  with  the  relative  proportion  of  deaths 
from  cancer  to  deaths  from  all  causes.  Each  amounted  to  65  per 
cent,  in  the  year  1900.  Although  the  present  generation  looks 
after  the  aged  better  than  in  years  gone  by,  there  is  vet  room  for 
great  improvement  which,  as  in  the  past  so  also  in  the  future, 
will  lead  to  deaths  l)eing  transferred  to  an  accurate  cause  of 
death,  in  many  cases  to  cancer. 

Up  till  now  I  have  confined  my  remarks  mainly  to  England 
but  all  the  reservations  and  criticisms  made  in  discussing  the  real 


REVIEW    OF    RECENT    CANCER    RESEARCH 


13 


or  apparent  increase  of  cancer  in  that  country  apply  with  added 
force  to  all  other  countries.  In  Greece,  Portugal.  Turkey,  and 
Russia,  no  statistics  exist.  For  France.  Denmark,  Sweden, 
Roumania,  and  Bulgaria  they  are  compiled  only  for  the  towns. 

Death-rates  per  i,ooo  Persons  Living,  iSSi-igog 


Countries  (Arranged  in  Order 
of  Crude  Rates  in  1901-5) 


Switzerland 

The  Netherlands  .  .  .  . 
England  and  Wales  . . 

Scotland 

Austria 

Victoria 

Ireland 

New  Zealand 

South  Australia 

Prussia 

New  South  Wales  .  .  . 

Belgium 

Queensland 

Tasmania 

Italy 

Ontario,  Province  of. 
Western  Australia .  .  . 

Spain 

Hungary 

Servia 


Crude  Rates 

Corrected  Rates 

1881- 

1886- 

1891- 

1896- 

I90I- 

1901- 

1906 

1907 

1908 

1909 

1885 

1890 

i89r 

-1900 

1905 

1905 

1.03 

1. 14 

1.22 

1.27 

1.30 

1. 10 

1. 12 

1.06 

I. II 



0.60 

0.70 

0.81 

0.92 

0.97 

0.85 

0.88 

0.89 

.0.90 
0.92 

0.90 

0-55 

0.63 

0.71 

0.80 

0.86 

0.86 

0.92 

0.91 

0.95 

0.54 

0.62 

0.69 

0.77 

0.84 

0.83 

0.94 

0.94 

0.94 

— 

0.44 

0.50 

0.59 

0.69 

0.74 

0.69 

0.73 

0.72 

0.72 

— 

0.45 

0.53 

0.62 

0.69 

0.74 

0.76 

0.77 

0.82 

0.81 

0.82 

0.38 

0.43 

0.49 

0.58 

0.69 

0.56 

0.64 

0.62 

0.62 

0.65 

0.30 

0.42 

0.52 

0.59 

0.67 

0.75 

0.79 

0.82 

0.79 

0.82 

0.32 

0.39 

0.48 

0.56 

0.67 

0.76 

0.84 

0.80 

0.77 

0.86 

0.34 

0.41 

0.50 

0.57 

0.6s 

0.64 

0.69 

0.72 

0.73 

0.74 

0.27 

0.36 

0.43 

0.54 

0.64 

0.80 

0.85 

0.87 

0.84 

0.90 

— 

— 

— 

— 

0.582 

0.49 

0.49 

0.51 

0.54 

— 

0.25 

0.27  jo.34 

0.44 

0.57 

0.79 

0.76 

0.90 

0.71 

0.83 

— 

0.49 

0.49 

0.5s 

0.56 

0.68 

0.63 

0.77 

0.82 

0.82 

— 

0.43' 

0.44 

0.51 

0.5s 

0.45 

0.51 

0.50 

0.53 

0.53 

0.21 

0.29 

? 

0.44' 

0.52 

— 

— 

— 

— 

— 

0.33    0.41 

0.31 

0.31 

0.45 

0.74 

0.98 

0.83 

0.86 

1.09 

—       — 

— 

— 

0.44 

0.38 

0.41 

0.41 

0.44 

0.44 

—    ,    — 

— 

o.30> 

0.39 

0.38 

0.39 

0.41 

0.42 

0.43 

— 

— 

0.061 

0.08 

O.IO 

— 

— 

— 

— 

— 

Therefore  only  the  crudest  comparison  on  the  basis  of  the  num- 
ber of  deaths  per  looo  li\'ing  is  ])(issil)le,  and  it  is  pn)hable  that 
this  comparison  as  set  out  in  the  accompanying  ta])le  is  valueless. 

In  all  probability  the  figures  in  this  table  illustrate  simply  the 
degree  of  the  development  of  the  statistics  of  the  several  coun- 
tries and  do  not  reveal  real  differences  in  the  incidence  of  cancer. 
Read  from  above,  downwards,  they  indicate  the  increasing  worth- 
lessness  of  the  statistics  from  Switzerland,  where  a  compulsory 
medical  inspection  of  the  dead  obtains,  to  Ser\ia  where  they 
probably  have  no  value  at  all.  l\ead  from  left  to  right,  they  in- 
dicate mainlv  the  impro\-ement  in  the  statistics  of  each  Cf^untry. 
The  figures  for  tlie  Tnited  Slates  ha\e  been  .already  referred  to. 

Allhougli  comparisons  l)(.-l\\een    l""nropcan  cnnniiirs  are  use- 

^  Four  years. 
-  3  years. 


14  REVIEW    OF    RECENT    CANCER    RESEARCH 

less,  the  study  of  cancer  in  widely  removed  peoples  has  had  results 
of  importance.  It  has  been  definitely  proved  that  the  idea  that 
cancer  is  rare  or  does  not  occur  at  all  in  certain  parts  of  the  earth 
is  false,  c.  g.,  Egypt,  India,  Japan.  In  Japan  there  are  30,000  to 
40,000  deaths  a  year,  though  the  inhabitants  are  mainly  rice 
eaters,  and  there  is  no  discoverable  difference  between  the  parts 
of  that  country  where  fish  enters  more  largely  into  the  diet. 
In  India,  cancer  is  by  no  means  rare  either  in  vegetarian  or  other 
castes.  Of  course  no  conclusions  as  to  the  relative  frequency 
of  cancer  is  possible,  but  it  has  been  ascertained  that  diet,  climate, 
and  race,  if  not  of  no  importance  at  all,  are  of  little  moment  in 
comparison  with  chronic  irritation.  Here  again  it  is  not  by 
lumping  all  cases  of  cancer  together,  but  by  separately  consider- 
ing the  several  sites  and  organs,  that  advances  have  been  made. 
Through  chronically  irritating  certain  parts  of  the  body  by  prac- 
tising certain  exotic  native  customs  the  dwellers  in  widely  re- 
moved parts  of  the  earth  have  performed  unintentional  experi- 
ments of  the  highest  value,  in  that  they  have  thereby  changed 
the  anatomical  distribution  of  cancer  as  it  is  known  in  the  bodies 
of  Europeans.  Epithelioma  of  the  skin  of  the  abdomen,  prac- 
tically unknown  in  Europe,  is  very  common  in  Kashmir,  where 
the  Kangri  or  fire-basket  filled  with  burning  charcoal  is  carried 
round  the  abdomen  and  leads  to  repeated  burning.  Carcinoma 
of  the  mouth,  so  rare  in  women  although  not  rare  in  men  in 
Europe,  is  as  common  in  women  in  certain  parts  of  India  as  in 
men.  In  China  rice  is  eaten  very  hot  by  the  men.  who  are  served 
first  In-  the  women.  The  latter  get  the  rice  cold ;  they  escape  the 
carcinoma  of  the  oesophagus  so  common  in  the  men.  In  the 
regions  of  the  Upper  Nile  cases  of  melanotic  sarcoma  are  not 
uncommon  on  the  sole  of  the  foot  and  always  subsec^uent  upon 
the  injury  due  to  the  entrance  of  a  thorn.  The  fullest  biological 
importance  is  given  to  these  observations  by  corresponding  ob- 
servations on  animals ;  for  example  in  India,  where  cattle  are 
harnessed  by  the  right  horn,  epithelioma  develops  in  consequence 
at  the  root  of  that  horn  but  ne\-er  at  the  root  of  the  left  one. 
In  parts  of  England  and  Ireland  cancer  is  very  common  in  the 
liver  of  the  cow,  alwavs  associated  with  cirrhosis  of  that  oroan. 


REVIEW    OF    RECENT    CANCER    RESEARCH  15 

Thus  comparative  investigations  have  given  a  new  and  enhanced 
importance  to  the  forms  of  chronic  irritation — kipus-scar,  burn- 
scar,  bilharzia,  etc. — long  known,  or  new,  hke  the  X-rays.  Like 
the  older  forms  of  irritations  these  newer,  or  hitherto  neglected 
forms  of  irritation,  have  nothing  in  common,  unless  it  be  argued 
they  permit  the  entrance  of  a  ubiquitous  cancer  parasite. 

In  considering  the  importance  of  irritation  in  Europe  and 
America  again,  it  is  necessary  to  consider  the  different  parts  of 
the  body  separately.  In  the  case  of  the  different  parts  of  the 
intestinal  canal,  the  curves  of  relative  frequency  cross  at  the 
stomach  in  both  sexes ;  above  the  stomach  cancer  is  more  common 
in  the  male,  below  it  more  common  in  the  female,  both  in  the 
national  statistics  and  in  hospital  statistics  of  England.  This 
circumstance  may  not  be  without  relation  to  the  different  habits 
of  the  two  sexes,  the  male  irritating  the  upper  half  of  the  canal 
by  smoking,  alcohol,  gulping  his  food,  etc.,  more  than  the  female, 
who  is  more  prone  to  the  chronic  irritation  of  constipation. 
Moreover,  the  unwillingness  or  inability  of  women  to  nurse  chil- 
dren may  not  be  unconnected  with  the  increase  in  the  number 
of  deaths  recorded  from  cancer  of  the  breast.  The  increase  for 
cancer  of  the  tongue  in  men  and  the  stomach  and  intestines  in 
both  sexes,  therefore,  should,  perhaps,  not  be  dismissed  as  due 
merely  to  improved  diagnosis  and  certification  of  the  causes  of 
death. 

The  importance  of  considering  different  sites  apart  can  also 
be  argued  on  a  comparative  basis.  In  surveying  the  incidence  of 
cancer  in  the  vertebrate  kingdom,  one  has  been  struck  by  the 
fact  that  certain  forms  of  cancer  appear  to  preponderate  in  differ- 
ent classes.  It  is.  of  course,  obvious  that  the  incidence  of  cancer 
in  re])rcsentati\es  of  the  diff'erent  zoological  classes  must  differ, 
since,  c.  c/.,  structures  peculiar  to  mammals  are  absent  in  other 
vertel)rates.  Ihit  if  we  consider  the  mammalia  themselves,  it 
api)ears  probal)lc  that  some  species  are  very  liable  to  forms  of 
cancer  from  which  others,  even  nearly  allied,  are  relatively  or 
altogether  exempt,  as  illustrated,  r.  </.,  by  the  \'ariations  in  the 
fre([uencv  with  which  cancer  of  tlic  uterus  or  maniina  (u-curs. 
Cancer  of  the  breast,  so  common  in  tlie  human   female,  is  also 


16  REVIEW    OF    RECENT    CANCER    RESEARCH 

common  in  the  mouse  and  dog,  but  practically  unknown  in  the 
cow  which,  however,  suffers  quite  frequently  from  primary 
ofrowths  of  the  liver  and  adrenal.  These  tendencies  are  so 
constant  that  it  is  difficult  to  escape  the  conclusion  that  they 
depend  on  innate  characters  which  are  hereditarily  transmissible, 
and  there  can  be  no  doubt  as  to  their  etiological  importance, 
although  we  cannot  yet  penetrate  to  their  meaning. 

Even  in  the  same  species  we  meet  with  similar  idiosyncrasies, 
c.  g.,  in  the  greater  liability  of  grey  than  of  other  horses  to  mela- 
notic sarcoma.  It  may,  of  course,  be  argued  that  these  peculiar- 
ities of  incidence  of  the  disease  are  determined  by  peculiar  en- 
vironment or  by  the  use  to  which  the  organs  are  put  in  different 
species,  although  this  would  hardly  hold  for  gre}^  as  contrasted 
with  other  horses,  the  disease  in  question  affecting  only  the  pig- 
ment-cells of  the  skin.  If  we  compare  the  tame  albino  mouse 
with  the  wild  grey  mouse,  the  incidence  of  cancer  is  parallel  in 
them,  although  the  two  varieties  live  under  very  divergent  condi- 
tions; therefore  the  liability  of  the  mouse  to  carcinoma  of  the 
mamma  appears  to  be  due  to  an  innate  tendency. 

When  we  compare  the  large  natural  groups  of  vertebrates, 
or  even  the  species  of  the  mammalia,  the  grounds  on  which  we 
may  assume  that  differences  in  the  incidence  of  cancer  are  innate 
and  hereditarily  transmitted  appear  safe.  But  when  we  come  to 
compare  the  differences  in  the  incidence  of  cancer  in  the  individ- 
uals of  a  species  we  are  not  on  such  certain  ground. 

I  must  now  preface  what  I  have  to  say  about  the  experimental 
study  of  the  biology  of  the  tumour  cell  by  a  brief  account  of  in- 
vestigations in  which  the  statistical  and  experimental  methods  are 
combined,  inasmuch  as  the  latter  method  is  employed  to  elucidate 
a  problem  statistics  have  precised. 

In  the  first  place  it  was  necessary  to  ascertain  if  the  reason 
why  cancer  occurred  with  greater  frequency  in  the  old  than  in  the 
young  was  due  to  a  constitutional  change  suitable  for  the  growth 
of  the  cancer  cells.  It  was  found  at  once  that  young  animals 
were  more  suitable  for  inoculation  and  for  growth.  It  was  there- 
fore made  evident  that  the  origin  of  cancer  was  distinct  from  its 
continued  growth  and  the  influence  of  senescence  was  bound  up 


REVIEW    OF    RECENT    CANCER    RESEARCH  17 

with  the  origin  and  not  a  constitutional  change  favourable  to 
continued  growth  of  the  tumour  once  it  had  developed.  This 
result  as  to  suitability  for  growth  had  to  be  followed  up  further, 
but  in  order  to  do  so  a  stock  of  mice  liable  to  cancer  had  to  be 
made  available. 

The  influence  of  heredity  is  undetermined  and  perhaps  not 
capable  of  settlement  in  men  owing  to  the  length  of  life.  For 
upwards  of  eight  years  atempts  at  Ijreeding  mice  from  cancerous 
parents  have  been  made.  Until  1909  no  result  was  obtained 
showing  that  cancer  had  thereby  become  a  more  frequent  occur- 


31    months 
over  IS 
Fig.  6. — Percentage  of  deaths  from  mamniary  carcinoma  to  deaths  from 
all  causes  at  successive  3-monthly  age-periods  in  female  mice  of  recently  can- 
cerous ancestry    (mother,  grandmothers)    ,   compared   with   the   same 

ratio  in  female  mice  having  more  remote  cancerous  ancestry  (mother  and 
grandmotiicrs  non-cancerous) 

rence.  Many  gcncrati(jns  of  mice  have  now  l)ecn  under  observa- 
tion in  whom  upwards  of  800  tumours  have  developed  naliu'ally. 
The  accom[)an}ing  curve  giving  the  results  of  Murray's  later 
observations  show  how  much  more  frequent  cancer  of  the 
mamma  is  in  mice  whose  mothers  or  grandmotliers  or  all  three 


18 


REVIEW    OF    RECENT    CANCER    RESEARCH 


suffered  from  cancer.  It  must  be  noted  that  this  result  has  only 
been  ol)tained  by  an  amount  of  inbreeding  and  of  concentration 
of  the  hereditary  factor  which  occurs  very  rarely,  if  at  all,  in  the 
human  subject.  In  effect  the  observations  tend  to  show  that 
although  there  is  an  hereditary  factor,  in  all  probability  it  is  not 
of  sufficient  moment  to  cause  alarm  as  regards  human  beings. 
The  possession  of  a  stock  of  mice  with  this  higher  susceptibility 
permitted  another  experimental  method  to  be  resorted  to,  in 
order  to  discover  any  constitutional  peculiarities  of  the  animals 
and  the  relation  obtaining  between  the  tumour  and  the  animal  in 
which  it  arose.  Normal  and  cancerous  mice  of  different  ages 
and  of  known  ancestry  have  been  compared  as  regards  their 
suitability  for  inoculation.  In  regard  to  the  greater  suitability 
of  young  than  of  old  mice  for  inoculation  and  growth,  no  differ- 
ence exists  between  mice  of  long  cancerous  pedigree  and  mice 
devoid  of  a  cancerous  ancestry.  The  absence  of  any  such  differ- 
ence led  to  efforts  to  ascertain  if  cancerous  mice  were  constitu- 
tional similar  among  themselves  or  behaved  in  an  individual 
manner  towards  the  growth  of  cancer.     The  method  was  to  inoc- 


Mice  with  Spontaneous 
Cancer 


Normal  Mice 


Spontaneous  Tumour  A. 
"        B. 


Spontaneous  Tumour  C . 
D. 
E. 


A  B 

+  - 

-  + 

C  D 

+  - 

-  + 


-     0/35 
+     3/35 


} 


+ 


o/iooo 

+   4/26 


ulate  the  spontaneous  tumours  into  other  mice  having  spon- 
taneous tumours,  and  also  to  re-implant  them  into  the  mice  in 
which  they  had  arisen.  The  results  of  Haaland's  observations 
gi\'en  in  the  accompanying  table  show  how  great  is  the  difference 
between  re-inoculating  a  tumour  into  its  own  mouse  and  inoculat- 
ing it  in  any  other  mouse,  wliether  normal  or  suffering  naturally 
from  a  growth  of  its  own.  Re-inoculation  with  an  animal's  own 
tumour  succeeds  in  100  per  cent,  if  there  Ije  no  untoward  acci- 
dent. On  the  other  hand,  success  is  as  rare  in  other  cancerous 
mice  as  it  is  in  normal  animals.     Thus  it  was  proved  that  cancer 


REVIEW    OF    RECENT    CANCER    RESEARCH  19 

does  not  grow  because  of  a  constitution  or  a  soil  suitable  for  the 
growth  of  cancer,  in  general.  A  lowering  of  the  affinity  of  the 
body  cells  as  a  whole  for  food-stuffs  with  retention  of  a  higher 
avidity  by  the  tumour  cells  would  not,  for  example,  explain  can- 
cer. It  was  made  evident  that  the  origin  and  growth  of  cancer 
involved  problems  individual  to  each  animal,  and — in  the  absence 
of  any  evidence  of  a  constitutional  change  favourable  to  the 
growth  of  cancer — it  appears  possible  that  the  hereditary  influ- 
ence is  rather  one  of  the  tissue  affected  than  any  change  in  the 
body  as  a  whole.  This  conclusion  as  to  indixiduality  has  been 
borne  out  by  other  observations.  Normal  mice,  young  and  old, 
have  been  housed  in  the  same  room  for  the  length  of  life,  to- 
gether with  mice  highly  susceptible  to  and  constantly  developing 
cancer ;  but  no  excess  of  cases  occurred  in  the  former.  They 
were  no  more  lialjle  to  cancer  than  mice  kept  free  from  all  such 
outside  influence.  The  same  negative  result  has  also  been  ob- 
tained where,  during  many  years,  as  many  as  10,000  to  20,000 
mice  inoculated  with  cancer  have  been  kept  in  one  room  together 
with  normal  animals.  Tumours  did  not  develop  with  any 
greater  frequency  than  in  animals  not  so  exposed.  These  results 
agree  with  those  for  men,  since  it  cannot  be  shown  that  the  den- 
sity of  population  has  any  influence  on  the  frequency  of  cancer 
in  contrast  with  its  marked  influence  in  the  case  of  tuberculosis. 

The  bearing  of  all  this  statistical  study  on  etiology  is  that  it 
gives.no  sort  of  indication  that  a  problem  of  infection  is  in- 
volved, although  the  importance  of  chronic  irritation  and  of  an 
inherited  and  possibly  a  tissue  susceptibility  is  clearly  brought  out. 

The  irritants  having  nothing  in  common,  it  seemed  rational 
for  this  and  other  reasons  t(^  seek  for  the  common  factor  in  prop- 
erties of  the  tumour  cells  tliomselves,  and  to  follow  up  the  unin- 
tentional experiments  of  native  races,  by  carefully  observing  the 
l)ehaviour  of  tumour  cells  during  years  of  prolonged  prolifera- 
tion, more  es])ccially  because  at  the  \  ery  beginning  ol  our  ex- 
periments we  noic(l  snch  niai-ked  \arialions  dccurring  f]-i>m  lime 
to  time  in  Inniors  of  the  same  strain,  lliat  a  person  ignorant 
(•f  its  historv  would  certainlv  have  held  thev  were  reallv  distinct 


Lecture  II. 

Experimental  Study  of  Tumor  Cells 

Up  to  the  present,  tumours  of  mammals  when  transplanted  into 
other  individuals  have  grown  progressive!}'  only  in  other  animals 
of  the  same  species.  An  inoculation  of  a  tumour  from  another 
species  does  not  alter  the  suitahility  of  an  animal  for  the  subse- 
quent transplantation  of  a  tumour  of  its  own  species.  The 
claim  has  been  made  that  resistance  could  be  produced  in  this 
latter  way;  but  our  very  extensive  observations  show  that  the 
constant  result  is  as  stated,  whereas  the  occasional  and  apparent 
protection  obtained  after  inoculation  of  strange  tumour  is  ex- 
plicable by  accidental  circumstances.  If  the  animals  are  ill  from 
any  cause,  c.  g.,  from  a  too  large  inoculation  dose,  Sepsis,  enteritis, 
etc.,  they  are  rendered  less  suitable  for  transplantation,  and  an 
appearance  of  resistance  is  produced.  This  point  is  of  impor- 
tance because  the  apparent  protection  after  inoculation  of  a 
tumour  of  a  strange  species  has  been  used  as  evidence  that  the 
tumours  of  different  species,  especially  the  sarcomata,  have  some- 
thing in  common  in  the  nature  of  a  parasitic  etiology.  As  a 
matter  of  fact  the  inoculation  of  mice  with  transplantable  rabbit 
or  rat  sarcoma  has  no  effect  upon  a  later  inoculation  of  mouse 
sarcoma.  Thus,  the  specificity  of  cancer  is  ]:)ro\-ed  in  two  ways: 
by  absence  of  power  to  grow  progressively  in  a  strange  species 
and  by  failure  of  a  strange  tumour  to  induce  resistance  to  homol- 
ogous inoculation.  The  specific  character  of  tumours  is,  how- 
ever, brought  out  even  more  clearly  ])y  the  induction  of  resistance 
by  means  of  the  normal  tissues  of  the  same  species,  but  not  of  a 
strange  species.  Even  in  the  same  species  biological  differences 
between  tumours  can  be  detected  by  these  methods.  If  a  tumour 
be  inoculated  which  takes  in  loo  per  cent,  and  all  the  resulting 
tumours  soon  undergo  spontaneous  healing,  the  animals  will  then 
be  found  to  be  completely  protected  against  a  re-inoculation  of 

20 


REVIEW    OF    RECENT    CANCER    RESEARCH 


21 


the  same  tumour.  Against  other  tumour  strains  there  may  be 
complete  or  incomplete  protection,  or,  indeed,  there  may  be  no  pro- 
tection at  all.  In  this  connection  there  appears  to  be  some  dif- 
ference between  carcinoma  and  sarcoma,  and  although  the  sub- 
ject requires  further  investigation  it  seems  that  sarcoma  protects 
better  against  carcinoma  than  the  latter  does  against  sarcoma. 
Thus,  there  is  a  degree  of  immunity  which  is  common  to  all 
tumours  of  a  species,  a  pan-immunity  in  Ehrlich's  sense,  and 
degrees  of  immunity  which  are  specific.     The  pan-immunity  de- 


1 

44E. 


Lmbrya   Zlkin 1  umar LanTral  9> 

Fig.  7.1     Similarity  of  resistance  produced   by  tumuur  and  liy  normal   tissue 

respectively. 

I)ends  on  the  properties  of  the  tumours  as  tissues  of  the  species ; 
the  specific  differences  in  the  tumours  will  be  considered  later. 
The  high  degree  of  protection  produced  by  normal  tissue  is  most 
remarkable,  as  the  accompanying  curves  from  W'oglom's  experi- 
ments show.     The  two  cur\es  run  parallel  and  the  coni[)arison 


1  Reprinted  hy  courtesy  of  the  Jminuil  of  lixf'criiiiciitiil  M i'Jiciiu'. 


22  REVIEW    OF    RECENT    CANCER    RESEARCH 

established  between  tumour  and  normal  tissues  shows  that  the 
resistance  induced  by  tumour  is  not  due  to  any  foreign  agency. 
^Mlen  normal  tissue  is  inoculated,  necrotic  tissue  and  other  irreg- 
ularities insepara1)le  from  tumour  are  avoided;  therefore,  too 
much  weight  must  not  be  laid  upon  the  fact  that  normal  tissue  in- 
duces a  higher  degree  of  resistance  than  does  tumour  tissue. 
Nevertheless,  this  difference  may  have  some  etiological  signifi- 
cance and  will  be  referred  to  again. 

In  order  to  induce  resistance  the  normal  and  tumour  cells 
must  be  ali\'e.  If  their  vitality  be  destroyed  in  any  way,  e.  g., 
by  heat,  chemical  means,  mechanical  crushing,  or  radium,  the 
power  to  induce  resistance  is  entirely  lost.  Unable  to  separate 
this  property  from  the  life  of  the  cells,  we  are  in  a  position  simi- 
lar to  that  obtaining  before  the  ferment  action  of  yeast  was 
separated  from  the  living  cells. 

The  resistant  change  is  spread  throughout  the  body,  and  state- 
ments to  the  effect  that  a  subcutaneous  inoculation  will  not  pro- 
tect against  a  later  inoculation  into  an  internal  organ  are  erron- 
eous. The  protection  is  just  as  effective  there,  and,  indeed,  can 
be  shown  to  be  active  even  in  the  blood.  If  tumour  emboli  be 
induced  in  the  lungs  of  mice  immunised  with  normal  or  tumour 
tissue,  the  emboli  do  not  develop  into  tumours  as  in  normal  ani- 
mals, but  remain  confined  within  the  vessel  walls  and  degenerate. 
It  is  evident  that  complete  protection  can  be  conferred  against  the 
introduction  of  the  cancer  cell  from  without,  so  that  were  cancer 
spread  in  this  way  or  communicated  from  individual  to  individual 
as  has  been  alleged  in  so-called  cancer  a  deux,  we  should  already 
be  alile  to  confer  exemption  on  the  communitv. 

The  foregoing  results  have  reference  only  to  testing  animals 
by  an  inoculation.  Once  a  tumour  has  established  itself  the  resist- 
ance has  much  less  effect,  except  in  the  case  of  tumours  which  in- 
duce resistance  to  their  own  growth  and  in  consequence  undergo 
spontaneous  healing.  .Vn  animal's  own  tissues  do  not  induce  any  re- 
sistance against  tumour  inoculation.  Animals  already  bearing 
trans])lanted  tumours  can  l)e  immunised  against  a  second  inocula- 
tion, so,  also,  mice  with  spontaneous  tumours  can  be  protected 
against  the  inoculation  of  a  transplantable  tumour;  but  in  the 


REVIEW    OF    RECENT    CANCER    RESEARCH  23 

latter  case  the  resistance  is  without  any  effect  upon  an  inocula- 
tion of  an  animal  with  its  own  spontaneous  tumour.  The  prog- 
ress of  spontaneous  tumours  and  the  formation  of  metastases  is 
in  no  way  affected  by  any  of  these  methods.  ]\Iice  which  have 
been  kept  immunised  for  months  will  develop  spontaneous  tu- 
mours of  their  own,  which  fact  also  speaks  for  the  endogenous 
origin  of  cancer.  These  facts  discredit  all  claims  to  cure  cancer 
b}'  means  of  autolytic  products,  vaccines,  or  immune  sera.  The 
importance  of  the  resistance  that  can  be  induced  against  inocula- 
tion is  purely  biological,  enabling  us  to  obtain  information  on 
some  hitherto  hidden  qualities  of  the  tumour  cell  and  its  relation 
to  the  organism,  and  leading  to  the  inevitable  conclusion  that 
every  case  of  cancer  is  a  problem  individual  to  the  person  in 
whom  it  develops.  They  have  no  therapeutic  value  as  yet  and  it 
is  not  apparent  if  they  ever  will  have  any.  Furthermore,  they 
throw  no  light  on  the  great  frecjuency  of  cancer. 

Other  observations  to  which  I  have  already  referred  have 
explained  the  relative  frecjuency,  in  different  human  races,  of 
certain  forms  of  cancer  associated  with  chronic  irritation.  Sim- 
ilar conditions  were  also  noted  for  animals  and  the  fact  also 
alluded  to  that  cancer  has  special  predilections  for  certain  mam- 
malian organs  which  are  exempted  in  other  species. 

I  pass  now  to  consider  the  results  of  the  prolonged  propaga- 
tion of  tumours  of  the  mouse,  wliich  is  peculiarly  liable  to  can- 
cer of  the  mamma.  This  is  a  Ijiological  problem  of  as  much  im- 
portance as  the  great  liability  of  the  human  female  to  cancer  of 
the  Ijreast.  In  the  case  of  the  mouse,  Haaland  has  shown  how 
common  is  chronic  inllammation  in  the  mamma  of  old  females 
and  has  pointed  out  one  cause.  \\'/..,  the  presence  of  nematodes, 
tliough  il  does  not  follow  lliat  this  is  the  only  cause.  The  chronic 
inllammation  is  associated  w  itli  hy|)ertrophic  nodules  and  adenoma- 
tous and  cancerous  changes  in  the  ei)ithelium  in  all  combinations. 
A  similar  combination  occurs  in  the  liver  of  cows,  where  cirrhosis, 
h}'pertropln'c  nodules,  adenoma,  and  c.nrcinoma — witli  extensi\e 
metastases  in  the  lungs  and  lymph  glands — are  frequently  com- 
l)ined.  Tiie  cirrhosis  is  here  associated  with  the  presence  of 
li\er-llukes  in  the  l)ile  duels,  1)ut  it  is  1)\-  n^  means  certain  tliai  the 


24  REVIEW    OF    RECENT    CANCER    RESEARCH 

cirrhosis  is  not  due  to  some  chemical  substance  absorbed  from  the 
food.  Thus,  the  more  comparative  the  study  of  chronic  irrita- 
tion becomes,  the  more  it  increases  in  importance  as  a  mediate  or 
indirect  cause  of  certain  forms  of  cancer.  It  is  ahnost  certain 
that  an  irritant  effective  in  one  species  of  mammal  will  not  be  an 
eft'ective  /.  c,  indirect,  etiological  factor  in  another  species.  The 
forms  of  irritation  are  manifold;  they  have  nothing  in  common 
beyond  their  causing  cell  injury  and  their  induction  of  cell  prolif- 
eration. When  tumours  are  transplanted  the  cell  proliferation  is 
simply  prolonged  artificially,  and  in  reality  by  again  causing 
cellular  trauma  we  are  continuing  the  experiment  which  had 
occurred  naturally.  This  prolonged  propagation  of  tumours  has 
been  criticised  as  of  no  etiological  value,  but  I  shall  show  you 
how  greatly  it  has  added  to  knowledge,  and  that  by  observing 
the  behaviour  of  tumour  cells  over  a  prolonged  period  certain 
inferences  may  be  drawn  as  to  how  the  cancer  cells  were  likely 
to  behave  before  they  were  placed  under  experimental  condi- 
tions. The  longing  expressed  by  Goodhart  in  1875:  "What  a 
subject  for  Darwin  would  be  the  cells  of  a  cancer  if  only  they 
were  tangible;  how  the  immortal  pigeon  would  be  completely 
eclipsed,  while  the  hungry  pathologist  would  be  filled  with  food, 
if  we  could  observe  the  variation  of  tumours  under  judicious 
cultivation!"  has  now  been  gratified,  if  cancer  has  not  yet  found 
its  Darwin. 

For  more  than  ten  years  the  behaviour  of  a  large  number  of 
transplantable  tumour  .strains  has  been  carefully  noted.  The 
observations  fall  mainly  into  two  groups,  those  relating  to  mor- 
phology and  those  bearing  on  the  phenomena  of  growth.  It  is  im- 
possible to  consider  here  all  the  factors  concerned  in  the  first 
transference  of  a  spontaneous  tumour  to  normal  animals.  It  is  a 
true  transplantation,  the  daughter  tumours  developing  from  the 
tumour  cells,  whilst  the  host  supplies  the  connective  tissue  and 
vascular  scaffolding.  A  certain  selection  is  effected  of  those 
cells  adapting  themselves  to  the  strange  conditions  or  able  to  live 
under  them.  The  soil  acts,  as  it  were,  as  a  sieve  allowing  cer- 
tain cells  to  pass,  selecting  only  some  that  are  capable  of  growth. 
At  the  next  transplantation  these  have  increased  in  number,  and 


REVIEW    OF    RECENT    CANCER    RESEARCH  25 

by  the  third  or  fourth  passage  the  percentage  of  takes  reaches  a 
level  which  has  remained  constant  for  years  for  the  majority  of 
our  tumours,  when  grown  in  as  many  parallel  sister  strains  as 
possible.  Most  of  the  tumour  strains  show  as  yet  unexplained 
and  apparently  periodic  fluctuations  from  time  to  time.  There 
are,  however,  some  remarkable  exceptions  to  constant  behaviour 
and  to  them  special  reference  will  be  made. 

AMien  a  tumour  is  transplanted  it  undergoes  entire  histolog- 
ical disorganisation.  This  process  has  been  repeated  over  and 
over  again  every  se^■en  or  ten  days,  or  after  longer  intervals,  for 
years.  Assuming  that  the  only  common  factor  for  all  the  irri- 
tants associated  with  cancer  is  their  power  to  induce  proliferation, 
the  process  is  as  analogous  as  is  possible  to  the  chronic  prolifer- 
ation which  precedes  the  development  of  cancer,  always  bearing 
in  mind  that  it  is  the  read}-  made  tumcjur  or  cancer  cell  which  is 
being  studied.  Xutwithstanding  the  fact  that  we  are  not  produc- 
ing the  cancer  cell  at  will,  but  are  merely  studying  its  behaviour — 
since  it  is  clearly  demonstrated  that  the  cancer  cell  is  a  genealog- 
ical descendant  of  a  normal  cell — we  are  justified  in  assuming 
that  the  propagated  cancer  cell  will  behave  similarly  to  its  geneal- 
ogical ascendants  in  its  host  of  origin  provided,  of  course,  that  we 
largely  neglect  the  possible  influence  of  strange  environment. 

After  the  disorganisation  caused  by  transplantation,  it  is  nec- 
essary to  give  time  for  a  tumour  to  resume  its  normal  haljits. 
Therefore,  it  is  advisal)le  to  study  not  merely  the  material  pre- 
ser\-ed  at  the  time  of  each  transplantation.  Init  also  tuniour>  that 
have  grown  for  some  time.  It  is  then  found  that  the  char- 
acteristic histological  structure  is  reproduced  as  a  rule,  it  may  l)e 
very  rapidly,  or  it  may  be  only  after  prolonged  growth.  Tliis 
characteristic  diO'ercnliation  occurs  in  si)ite  of  the  fact  that  the 
connective  tissue  and  vascular  scaffolding  has  to  be  reproduced 
anew  by  eacli  fresli  liost,  taking  i)lace  with  e(jual  regularity  in 
adenoma,  cystic  papillifcroiis  carcinoma,  and  solid  carcinoma  of 
the  mamma,  as  well  as  in  squamous-cellcd  carcinoma  and  in  ade- 
noma of  the  sebaceous  and  preputial  glands.  The  latter,  notwith- 
standing vears  of  ])ropagation,  still  re|)roduces  a  structure  whicli 
cannr)t  l)e  distinguislied  under  tlie  microscojK'    from  tlic  normal 


26  REVIEW    OF    RECENT    CANCER    RESEARCH 

preputial  gland.  The  conclusion  clearly  follows  that  tumours 
which  histologically  are  "benign"  can  be  propagated  for  the  same 
length  of  time  as  those  which  are  devoid  of  all  differentiation  and 
are  in  current  terminology  histologically  "malignant."  Experi- 
ment therefore  supports  clinical  experience  in  its  inability  to 
establish  a  sharp  division  between  benign  tumours — for  which  a 
parasitic  etiology  is  not  assumed — and  the  malignant  new  growths 
for  which  a  parasitic  etiology  is  asserted  to  be  essential. 

Other  more  subtle  features  revealed  by  microscopical  tech- 
nique may  be  retained  unaltered,  c.  g.,  tumours  which  form  gly- 
cogen in  large  droplets  have  continued  to  do  so  for  years,  from 
the  spontaneous  tumour  onwards.  A  tumour  strain  which 
caused  a  sarcomatous  transformation  of  the  connective  tissue 
scaffolding  supplied  by  the  new  hosts  has  continued  for  six  years 
to  effect  this  change  in  every  mouse  in  which  it  has  grown  for  60 
days. 

In  1905,  attention  was  drawn  to  the  fact  that  the  propagated 
tumours  derived  from  a  single  parenchyma,  viz.  the  mammary 
epithelium,  varied  so  much  in  microscopical  appearances  that  a 
person  ignorant  of  their  life-history  would  declare  them  to  be  of 
distinct  primary  origin.  This  early  observation  led  to  the  ex- 
tensive propagation  of  a  large  number  of  tumour-strains  of  sepa- 
rate primary  origin,  as  many  as  86  strains  being  kept  in  propa- 
gation at  one  time,  many  of  them  in  several  parallel  sister  strains. 
The  net  result  is  that  the  histological  differences  present  at  the 
outset  of  propagation  of  tumours  arising  from  the  same  paren- 
chyma, remain  in  many  cases  constant,  and  are,  therefore,  to  be  re- 
garded as  true  variations  of  relative  constancy.  The  further  con- 
clusion may  be  drawn  that  the  change  which  occurs  in  the  trans- 
formation from  normal  to  the  cancer  cell  deeply  affects  the  cell 
mechanism,  and  not  only  in  one  way,  but  in  several  ways. 

Although  the  constancy  with  which  strains  maintain  their  his- 
tological features  is  most  noteworthy  the  exceptions  to  this  gen- 
eral rule  are  perhaps  of  even  greater  biological  significance. 
Two  s(|uamous  celled  carcinomata  have  grown  for  years  and 
have  always  shown  complete  differentiation;  but  another  one 
behaved   in   this   way   only   up  to   the  ninth   transplantation   and 


REVIEW    OF    RECENT    CANCER    RESEARCH  27 

has  grown  for  years  without  any  reappearance  of  keratinisation. 
A  fourth  tumour  of  the  same  kind  has  also  behaved  in  the 
latter  wav,  and  some  adenomatous  tumours  have  likewise  l!)St  all 
evidence  of  acinous  differentiation.  There  are  adenomatous 
tumours  which  have  exhibited  a  most  remarkable  histological 
change;  after  transplantation  there  is  the  usual  undifferentiated 
cell  mass,  but  areas  of  spindle  cells  appear  later,  indistinguish- 
al)le  histologically  from  spindle  celled  sarcoma,  which  later  differ- 
entiate again  into  typical  acini  and  reproduce  the  picture  of  the 
mother  tumour.  This  spindle  celled  appearance  may  also  become 
constant,  and  only  in  the  very  oldest  tumours  may  there  l)e 
found  evidence  of  the  tendency  to  acinous  dift'erentiation.  Sim- 
ilar morphological  changes  have  also  been  observed  among  the 
propagable  sarcomata.  An  osteo-chondro-sarcoma  has  been 
grown  in  two  parallel  strains.  One  shows  a  great  tendency  to 
necrosis  and  is  soft  to  the  touch,  the  other  feels  hard  and  forms 
much  collagen.  Both  strains  have  lost  all  tendency  to  form 
either  cartilage  or  bone,  and  cannot  be  identified  with  the  mother 
tumour  except  from  their  life  histories.  As  a  last  example  an 
adeno-carcinoma  which  has  been  grown  in  i8  parallel  sister 
strains  may  be  referred  to.  It  illustrates  alike  the  constancy 
and  the  variability  of  the  histological  structure  and  other  i)rop- 
erties  of  the  epithelium.  I'or  three  years  some  of  the  strains 
of  this  tumour  caused  irregularly  sarcomatous  transformation 
in  the  stroma,  and  the  transformation  was  to  spindle-,  round-, 
and  p()l\"mi)rph<)us-cclled  sarcoma.  Other  sister  strains  ])os- 
sessed  no  such  property  but  have  grown  as  pure  adeno-carcinoma 
or  as  pure  solid  carcinoma.  Now,  after  several  years,  all  the 
strains  have  lost  the  power  to  produce  sarcoma.  One  of  these 
strains,  altliougli  remaining  a  pure  cpilhclial  lum<iur.  grows  with 
a  spindle-celled  parenchyma  exhibiting  sligln  tendency  to  acinous 
formation  in  ver)'  old  tumours. 

l^Vom  these  observations  it  follows  that  the  niorphohtgical 
variability  of  tumour  cells  is  as  completely  demonstrated  as  is  the 
constancy  with  wiiich  they  may  retain  their  histological  features. 

The  phenomena  of  growth  are  c(|ually  interesting.  They 
lia\e  been  carcfulh-  noted  durin<j-  ten  \ears  for  s(tnie  So  tumour 


28 


REVIEW    OF    RECENT    CANCER    RESEARCH 


Strains.  At  one  end  of  this  series  there  is  a  strain  growing  in 
ever}^  animal  with  great  rapidity  and  forming  metastases  in 
over  80  per  cent,  of  the  mice.  At  the  other  end  there  are 
tumours  taking  also  in  100  per  cent,  but  also  completely  healing 
in  each  animal.  There  are  other  strains  which  take  in  a  very 
low  percentage  and  grow  very  slowly.  The  intermediate  tu- 
mours represent  the  utmost  variety  of  combinations  of  these 
features.  Tumours  which  take  in  100  per  cent,  but  which  all 
disappear  after  transitory  growth  resemble  normal  tissue  in  this 
respect,  although,  of  course,  normal  tissue  has  not  been  found 
capable  of  unlimited  propagation.     In  order  to  have  some  stand- 


ii 


Fig.  8.  Diagrammatic  comparison  of  rate  of  growth  of  various  tumor- 
strains  qn  the  basis  of  the  number  of  days  required  to  produce  i  grm.  of 
tissue  from  a  measured  dose  (0.2-0.3  grm.)  inoculated.  The  rate  of  growth 
of  embryonic  tissue  is  also  indicated  on  the  basis  that  the  mouse  embryo 
weighs  0.02-0.03  grm.  at  the  nth  day  of  gestation  and  at  birth  1-1.5  grm. 


ard  for  comparing  the  rates  of  growth  of  these  tumours  they  have 
been  contrasted  with  the  rate  of  growth  of  the  mouse  embryo  as 
shown  in  the  accompanying  diagram  (Fig.  8).  Ten  days  before 
birth  the  mouse  embryo  weighs  0.025  grm.  and  at  birth  about 


REVIEW    OF    RECENT    CANCER    RESEARCH  29 

I  grm.  For  years  all  tumuiir  strains  have  been  inoculated  in 
doses  of  0.025  ^"<i  the  developing  tumours  weighed  at  ten  days. 
This  method,  of  course,  does  not  permit  oi  exact  comparisons, 
but  it  permits  of  a  rough  comparison,  and  brings  out  the  fact  that 
the  tumours  show  all  rates  of  growth.  Some  may  be  said  to 
equal  the  rate  of  growth  of  embryonic  tissue,  others  fall  far 
short  uf  it.  This  is  one  more  experimental  proof  that  the 
progressive  growth  of  cancer  cannot  be  explained  by  analogy 
with  embryonic  growth. 

As  regards  the  relation  between  structure  and  rate  of  growth, 
it  can  be  stated  that  as  a  general  rule  the  most  rapidly  growing 
tumours  exhibit  least  e\idence  of  differentiation.  There  are 
exceptions  c.  g.,  when  a  tumour  devoid  of  all  differentiation  is 
also  one  of  the  most  slowly  growing,  or  when  a  well  developed 
acinous  structure  is  associated  with  rapid  growth.  Some  strains 
showing  full  differentiation,  c.  g.,  squamous-celled  carcint)ma  and 
adenoma  of  the  sebaceous  glands  grow  extremely  slowly. 

As  regards  dissemination,  the  frequency  of  lung  metastases 
varies  from  strain  to  strain.  In  general,  they  are  more  frequent 
for  rai)idly  growing  strains,  the  most  rapidly  growing  of  our 
carcinomata,  viz.,  strain  63,  giving  them  in  as  many  as  80  to  95 
l)er  cent,  of  the  mice  inoculated,  provided  the}-  li\'e  long  enough 
afterwards. 

The  comparison  of  rates  of  growth  given  above  for  dift'erent 
tumours  extends  over  many  years  and  permits  of  the  conclusion 
that,  for  most,  the  tyi)e  of  growth  is  constant,  once  the  earlier^ 
passages  have  been  got  over.  1die  features  of  growth  may  be  as 
I)ersistent  during  years  as  the  retention  of  histological  struc- 
ture. It  is  not  the  general  rule  for  a  gradual  increase  in  the  rate 
of  growth  to  lake  i)lace  from  the  slowest  to  the  most  rapid,  and 
in  several  instances  the  deliberate  attempt  to  attain  this  has  \\o\. 
been  successful.  It  seems  therefore  that  the  type  of  growth 
is  in  most  cases  a  primary  quality  of  tlie  tumour  cells,  imprinted 
on  them  at  the  time  of  the  cancerous  transformation;  like  the 
morphological  features  it  exhibits  a  number  of  varieties  of  rela- 
tive constancy.  'J'here  are,  however,  important  exceptions  where 
a  remarkable   change   has   taken   place.      In   some   cases   it    may 


30  REVIEW    OF    RECENT    CANCER    RESEARCH 

be  only  that  A\-here  tumours  were  lialjle  to  spontaneous  ab- 
sorption, this  event  is  postponed  for  a  longer  interval  after 
transplantation.  There  may  be  a  higher  percentage  of  takes. 
There  may  be  apparently  more  rapid  growth.  The  most  start- 
ling example  of  such  changes  is  seen  in  strain  63.  Several  sister 
strains  were  grown  from  the  original  material  and  two  are  still 
retained  in  propagation.  The  one  still  reproduces  to-day  the 
behaviour  characteristics  of  the  earliest  passages,  when  the  per- 
centage of  takes  and  the  rate  of  growth  were  moderate,  while  a 
large  number  of  tumours  underwent  spontaneous  healing.  The 
other  parallel  strain  grows  progressively  in  every  mouse  with 
great  rapidity,  and  never  shows  spontaneous  healing.  If  the 
mice  live  long  enough  most  of  them  show  metastases  in  the 
lungs.  These  experiments  show  that  just  as  it  may  be  impossible 
to  recognize  the  relationship  of  daughter  tumours  to  the  orig- 
inal material  owing  to  variation  in  the  histological  structure,  so 
also  the  variation  in  powers  of  growth  may  be  equally  great. 
The  conclusion  is  thus  arrived  at  that  during  the  prolonged 
propagation  which  is  ever  being  interrupted  by  the  trauma  of 
a  fresh  transplantation,  what  are  really  new  tumours  have 
arisen.  The  power  of  progressive  growth  and  of  dissemination 
may  be  so  completely  acquired  that  the  tumour-strain  behaves 
in  normal  animals  like  a  spontaneous  tumour  in  its  host  of  origin. 
In  other  words,  the  possible  influence  of  a  strange  environment 
can  be  left  out  of  account  in  this  instance.  It  appears  therefore 
that  the  study  of  propagated  tumours  has  thrown  a  little  fresh 
light  on  why  some  forms  of  cancer  may  arise  in  association  with 
chronic  irritation,  although  it  has  not  given  an  explanation  of  the 
differences  in  the  behaviour  of  normal  and  tumour  tissue.  The 
following  observations  have  however  also  taken  us  a  step  in  this 
direction. 

It  has  been  pointed  out  that  whereas  some  tumours  grow 
progressively  in  all  animals  and  form  metastases,  others  only 
grow  for  a  time  and  then  disappear,  and  also  that  all  intermediate 
stages  have  been  oljserved.  The  possession  of  such  a  compara- 
tive series  of  tumour-strains  has  made  it  possible  to  ascertain  one 
reason  for  the  difference  between  the  two  chief  groups  into  which 


KE\IE\V    OF    RECENT    CANCER    RESEARCH  31 

transplantable  tumours  may  be  di\ided.  The  experimental 
method  is  to  inoculate  a  tumour-strain  and  then  determine  the 
suitability  of  the  animal  for  a  secondary  inoculation.  The  re- 
sults were  at  first  contradictory,  but  the  extremely  careful  in- 
vestigations of  Russell  have  led  to  the  tumour-strains  being 
placed  into  two  chief  groups  corresponding  with  those  that 
grow  progressively  in  every  animal  and  those  which  after  transi- 
tory growth  undergo  spontaneous  healing  in  every  animal.  It 
has  been  clearl\-  demonstrated,  as  the  accompanying  lantern  slides 
show,  that  in  the  first  group  a  re-inoculation  is  always  successful; 
in  the  second  it  always  fails.  In  other  words,  the  first  group 
does  not  induce  any  resistance  to  a  secondary  inoculation,  and 
the  second  group  always  does  so.  The  conclusion  drawn  is  that 
the  first  groui)  floes  not  induce  resistance  to  its  own  growth, 
whereas  the  second  group  does  so  by  virtue  of  a  resistance  which 
it  induces  and  which  develops  concomitantly  with  the  growth  of 
tumours  after  transplantation.  In  the  intermediate  groups  of 
tumours  the  indixidual  reaction  of  the  animals  plays  a  more 
prominent  [)art  in  permitting  progressive  growth  in  one  instance, 
and  in  another,  in  leading  to  spontaneous  healing,  .\ttention  has 
alread}'  been  drawn  to  the  evidence  that  normal  tissue  induces 
a  higher  degree  of  resistance  than  does  spontaneous  tumour  tissue 
and  this  evidence  may  be  correlated  with  the  following  phenom- 
ena. As  has  been  shown,  normal  tissue  only  grows  transitorily 
after  transplantation  and  induces  resistance  to  subse([ucnt  lunionr 
inoculation.  Although  it  is  difficult  of  clear  demonstration,  the 
analogy  with  the  spontaneous  healing  of  some  tumour  strains 
makes  it  almost  evident  that  the  induction  of  this  resistance  is 
responsil)le  for  the  transitory  growth  of  normal  tissue.  It  is 
certain  that  the  induction  of  this  concomitant  resistance  or 
immunity  determines  the  occurrence  and  froiiucncy  of  the  spon- 
taneous healing  of  certain  tumour  strains,  and  the  (|uestioti 
arises  what  happens  when  from  tumour  material  capable  of  only 
transitory  growth,  there  are  grown  two  i)arallel  strains,  one  re- 
taining this  i)eculiarity  and  another  capable  i»f  progressive 
growth  and  of  metastasis-formation.  Careful  investigatiou  dem- 
onstrates that   the   power  of   progressive   growth   of  such   sister 


32  REVIEW    OF    RECENT    CANCER    RESEARCH 

Strains  is  acquired  because  they  have  lost  the  power  to  produce 
resistance  to  their  own  growth.  For  the  other  akernative,  that 
the  tumour  cells  might  acquire  a  power  to  overcome  the  resistance 
when  induced,  there  is  as  yet  no  evidence  whatsoever. 

It  would  be  easy  to  enter  into  a  hypothetical  discussion  of  the 
possible  bearings  of  these  facts  ascertained  for  transplanted 
tumour  cells,  upon  the  behaviour  of  tumour  cells  in  their  hosts 
of  origin.  It  seems,  however,  at  this  stage  sufficient  simply  to 
raise  the  question  of  whether  or  not  they  throw  new  light  upon 
the  regulation  and  control  of  normal  growth  and  the  unregulated 
and  limitless  growth  of  cancer. 

Before  concluding  it  is  necessary  to  refer  to  the  phenomenon 
of  natural  healing  in  spontaneous  tumours,  because  statements 
calculated  to  give  an  entirely  false  impression  have  been  widely 
disseminated.  For  about  700,  or  when  multiple  tumours  are  con- 
sidered, about  1000  spontaneous  tumours,  very  careful  observa- 
tion of  their  clinical  course  has  been  kept  for  weeks  and  months. 
Healing  has  not  occurred  in  i  per  cent.,  as  contrasted  with  trans- 
planted tumours,  for  which  it  can  be  obtained  in  any  desired  fre- 
quency by  simply  choosing  the  suitable  tumour-strains.  The 
processes  for  spontaneous  and  transplanted  tumours  may  be 
followed  histologically  and  they  exhibit  close  parallels.  There 
is  some  primary  change  in  the  tumour  cells,  which  although  not 
yet  understood,  appears  to  be  an  essential  preliminary.  Ulti- 
mately the  dead  tumour  cells  are  taken  up  by  phagocytes,  and 
the  formation  of  a  typical  scar  tissue  completes  the  process.  For 
transplanted  tumours  the  process  can  be  followed  in  detail  by 
examining  the  site  of  inoculation  in  animals  which  have  been 
made  highly  resistant  by  the  inoculation  of  tumour  or  normal 
tissue,  and  instituting  comparisons  with  the  corresponding  pe- 
riods after  inoculation  into  normal  animals.  There  are  then 
distinct  differences  observable  in  the  two  sets  of  animals.  In 
both  there  is  a  reaction  of  the  connective  and  vascular  tissues  of 
the  host.  Whilst  the  normal  animal  reacts  in  such  a  way  that 
the  implanted  piece  of  tumour  again  acquires  the  specific  stroma 
and  vessels  which  reproduce  the  original  structure  of  the  tumour, 
the  immune  animal  does  not  so  react.      In  the  latter  case  the 


REVIEW    OF    RECENT    CAXCER    RESEARCH  33 

specific  reaction  which  suppHes  the  characteristic  connective  tissue 
and  vascular  scaffolding  is  not  elicited.  The  tumour  cells  are  not 
at  once  killed,  indeed  they  may  be  observed  undergoing  mitotic 
division;  but  ultimately  they  die  and  suff'er  the  consequences 
of  the  formation  of  scar  tissue.  The  explanation  is  to  be  sought 
in  a  paralysis  of  the  chemotactic  influences  which  proceed  from 
the  tumour  cells. 

For  the  numerous  observations  which  ha\e  now  been  out- 
lined, it  cannot  be  claimed  that  they  afford  anything  approach- 
ing to  an  elucidation  of  the  problem  of  cancer.  It  is  only  cer- 
tain that  they  have  thrown  new  light  on  some  old  problems  and 
at  the  same  time  that  they  have  revealed  others  hitherto  unsus- 
pected. An  interesting  feature  is  the  relations  brought  out 
between  connective  tissue  and  epithelium,  c.  g.,  in  the  experi- 
mental induction  of  sarcoma  by  certain  carcinomata,  the  relation 
between  chronic  inflammation  of  the  mamma  of  mice  and  car- 
cinoma, cirrhosis  of  the  liver  and  carcinoma,  and  the  power  of  the 
transplanted  tumour  cell  to  mould  the  connective  tissue  and 
vascular  scaffolding  to  the  features  characteristic  of  the  original 
tumour.  In  sharp  contrast  is  the  failure  of  the  cancer  cell  to 
dominate  the  connective  tissue  in  the  immunised  animal  or  where 
spontaneous  healing  is  taking  place.  In  e\ery  one  of  the  experi- 
mental instances  of  the  relations  obtaining  between  the  cancer 
cell  and  the  connective  tissues,  it  is  the  influence  proceeding  from 
the  cancer  cell  itself  or  the  paralysis  of  this  influence  which  plays 
the  predominant  part.  The  same  part  seems  ti)  be  played  in  the 
natural  healing  of  spontaneous  tumours,  since  in  the  same  animal 
one  tumour  may  go  on  growing  while  another  is  healing.  We 
are  here  face  to  face  with  as  yet  unsolved  proJjlems  the  solution 
of  which,  without  doubt,  will  carry  us  further.  In  the  meantime 
we  have  not  succeeded  in  deflning  what  is  res[)onsible  for  the 
change,  and  it  is  therefore  most  surprising  that  attempts,  which  to 
\w\  nn'nd  appear  empirical,  are  being  made  to  cure  animals  ot 
transplanted  tumours.  The  claims  of  W'asscrmann  to  have  cured 
mice  of  transplanted  tumours  by  means  of  eosin-sclenium  com- 
pounds and  also  those  of  Neuberg  and  Caspari  to  have  attained 
the  same  end  bv  augmenting  what   is  described   as   the   norm;il 


34  REVIEW    OF    RECENT    CANCER    RESEARCH 

aiitolytic  process,  while  interesting  and  suggestive,  have  no  ra- 
tional basis  in  anything  I  have  related  to  you.  I  would  not  be 
misunderstood  as  being  a  person  hostile  to  what  in  the  terminol- 
ogy of  Ehrlich  is  known  as  chemotherapy  applied  to  cancer,  for  I 
have  the  honour  to  be  one  of  Ehrlich's  pupils,  and  at  the  same 
time  also  to  be  a  pupil  of  Fraser  who  with  Crum  Brown  was  the 
first  to  describe  the  relation  between  chemical  constitution  and 
physiological  action.  My  position  is  simply  this,  that  we  have 
not  yet  defined  where  and  how  an  interference  with  the  pernicious 
physiological  activities  of  the  cancer  cell  can  be  rationally  applied. 
Until  this  knowledge  is  attained  all  claims  to  cure  cancer  must 
remain  empirical,  although  it  does  not  follow  that  the  search' 
for  empirical  remedies  is  to  be  discouraged  in  such  persons  as 
care  to  undertake  it.  For  my  part,  I  counsel  the  continuation  of 
rational  experiment  into  the  mysteries  of  the  nature  of  cancer, 
and  I  trust  that  the  facts  I  have  set  out  as  the  result  of  the 
ten  years  of  investigation  by  my  colleagues  and  myself  have  con- 
vinced you  that  the  next  ten  years  of  experiment  will  reveal  yet 
other  new  facts  to  those  experimentalists  who  have  the  patience 
to  continue  these  laborious  enquiries. 


COLUMBIA   UNIVERSITY   LIBRARIES 

This  book  is  due  on  the  date  indicated  below,  or  at  the 
expiration  of  a  definite  period  after  the  date  of  borrowing,  as 
provided  by  the  library  rules  or  by  special  arrangement  with 


the  Librarian  in 

charge. 

1 

DATE  BORROWED 

DATE  DUE 

DATE  BORROWED 

DATE  DUE 

Q       ■ 

C28(n49)lOOM 

GAYLAMOUNT 
-  ^MPHLET   BINDER 

Manu/aelurtd  ty 

©AYLORD  BROS.  I««. 

Syracuce.  N.  Y. 

StocltUn,  Cilif. 


1 

:                                                               B29 
ho2e)l                                                    1914 

Bashford 

Reviev;  of   recent   ceaicer   research        \ 

DEC  11 

1950 

